Regio- and Stereodivergent Allylic Reductions of Bicyclic Piperidine Enecarbamate Derivatives (original) (raw)

Abstract

The particular nature of tetrahydropyrido[4,3-e]-1,4,2-dioxazines of type 1 allows the regio-and stereoselective obtainment of substituted N-carbamoyl tetrahydropyridines by common reducing agents. A completely novel, biologically active, bicyclic 1,3-diaza-4-oxa-[3.3.1]-nonene scaffold can be generated by the use of lithium triethylborohydride through an unprecedented cascade syn-SN2' reduction/carbamate reduction/cyclization reactions. The remarkable regioselectivity switches of allylic reduction process have been rationalized with the aid of computational studies. Tetrahydropyridines are important targets in synthetic organic chemistry due to their relevance as privilege structure in medicinal chemistry. 1 Therefore, considerable efforts have been devoted to the individuation of new methods for their regio-and stereoselective synthesis and functionalization. 2 However, a regio-and stereodivergent reduction of piperidine enecarbamates bearing an allylic leaving group has not yet been reported. The main reason for this shortcoming can be found in the relative instability of 1,2,3,4tetrahydropyridine derivatives containing common leaving groups at the C4-position. We recently became interested in the elaboration of nitroso cycloadducts derived from 2substituted-1,2-dihydropyridines, 3 easily accessible by addition of nucleophiles to activated pyridinium salts (eq. a, Scheme 1). 4,5 The [3,3]-hetero Cope rearrangement of the obtained nitroso Diels-Alder (NDA) cycloadducts has been reported to give 4a,7,8,8atetrahydropyrido[4,3-e]-1,4,2-dioxazines of type 1 (eq. a, Scheme 1). 6 We noticed that the study of their reactivity is limited to the NO reductive cleavage with Raney nickel to obtain racemic aminoarabinose and aminoaltrose derivatives. 6a On the other hand, palladiumcatalyzed allylic reduction have been used extensively in synthetic organic chemistry to

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References (42)

  1. -benzyl-8-cyclohexyl-8,8a-dihydropyrido[4,3- e][1,4,2]dioxazine-7(4aH)-carboxylate (1j). According to the general procedure, A2 (69 mg, 0.18 mmol), CuCl (3.7 mg, 0.037 mmol) in DCE (1.3 mL) reacted at 75 °C for 2 h. Subsequent flash chromatography (petroleum ether /AcOEt 8:2, Rf = 0.25) afforded the title compound as a white amorphous solid (40 mg, 58 %).
  2. H NMR (250 MHz, CD3CN, 65 °C) δ
  3. 9 Hz, 1H), 4.07 (s, 1H), 3.73 (s, 1H), 3.47 (s, 2H), 1.82 -1.40 (m, 6H), 1.32 -0.98 (m, 5H).
  4. C NMR (62.5 MHz, CD3CN) δ 156.6, 155.3 and 155.
  5. *, 136.9, 129.6, 129.5, 127.8, 127.6 and 127.
  6. *, 103.2* and102.7, 67.5, 65.5, 60.0, 54.0 and 53.
  7. *, 38.6, 37.9, 30.3, 26.8, 26.6, 26.5. [* minor rotamer]. HRMS (ESI) m/z [M + Na + ] Calcd for C21H26N2O4Na 393,1790, found 3931784. (4aR*,8S*,8aS*)-Methyl 3-benzyl-8-allyl-8,8a-dihydropyrido[4,3-e][1,4,2]dioxazine- 7(4aH)-carboxylate (1k). According to the general procedure, A3 (70 mg, 0.21 mmol), CuCl (4.2 mg, 0.043 mmol) in DCE (1.4 mL) reacted at 75 °C for 18h. Subsequent flash chromatography (hexanes /AcOEt 7:3, Rf = 0.25) afforded the title compound as a colorless oil (40 mg, 58 %).
  8. H NMR (250 MHz, CD3CN, 65 °C) δ 7.42 -7.20 (m, 5H), 6.85 (d, J = 8.4
  9. Hz, 1H), 5.96 -5.69 (m, 1H), 5.21 -5.02 (m, 2H), 4.97 -4.92 (m, 1H), 4.74 -4.65 (m, 1H),
  10. C NMR (62.5 MHz, CD3CN) δ 156.4, 154.6* and 154.3, 136.8, 134.2, 129.6, 129.4, 127.8, 126.7, 118.8, 102.1* and 101.7, 67.0, 66.4, 54.7, 53.9, 38.6, 34.7* and 34.3. [* minor rotamer]. HRMS (ESI) m/z [M + Na + ] Calcd for C18H20N2O4Na 351,1321, found 351.1317.
  11. -Phenyl-1-((1R*,5S*,9R*)-9-phenyl-4-oxa-1,3-diazabicyclo[3.3.1]non-6-en-3- yl)ethanone (6a). According to the general procedure, dioxazine 1a (365 mg, 1.0 mmol), LiBHEt3 (6.0 ml, 6.0 mmol) and THF (1.6 mL), 0°C for 1h. Subsequent flash chromatography (hexanes /AcOEt 8:2, Rf = 0.17) afforded the title compound as a white solid (321 mg, 76
  12. M.p. = 156-159 °C. 1 H NMR (250 MHz, CDCl3) δ 7.39 -7.20 (m, 10H), 6.07 -5.95 (m, 2H), 5.61 (d, 1H, J = 13.2 Hz), 4.99 -4.89 (m, 1H), 4.57 (d, 1H, J = 2.2 Hz), 4.48 (d, 1H, J = 13.
  13. Hz), 3.82 (d, 1H, J = 14.
  14. Hz), 3.55 (d, 1H, J = 14.7 Hz), 3.45 -3.18 (m, 2H).
  15. C NMR (62.5
  16. MHz, CDCl3) δ 172.3, 137.0, 129.7, 128.7, 128.5, 128.4, 128.0, 127.7, 126.9, 126.8, 119.4, 72.3, 65.7, 59.6, 47.6, 39.8. HRMS (ESI) m/z [M + Na + ] Calcd for C20H20N2O2Na 343.1422; Found 343.1421.
  17. -Phenyl-1-((1R*,5S*,8R*,9R*)-9-phenyl-4-oxa-1,3-diazabicyclo[3.3.1]non-6-en-3-yl- 2,2,8-D3)ethan-1-one (6a-D). According to the general procedure, dioxazine 1a (59 mg, 0.16 mmol), LiBDEt3 (0.97 ml, 0.97 mmol) and THF (0.28 mL), 0°C for 1 h. Subsequent crystallization (hexanes/AcOEt) afforded the title compound as a white solid (11 mg, 21.3%).
  18. M.p.=159 °C.
  19. H NMR (250 MHz, CDCl3) δ 7.41 -7.20 (m, 10H), 6.07 -5.94 (m, 2H),
  20. 31 (s, 1H).
  21. C NMR (62.5 MHz, CDCl3) δ 172.3, 137.1, 137.0, 135.1, 129.7, 128.5, 128.3, 127.6, 126.9, 126.7, 119.4, 72.3, 59.5, 47.25 (J = 21.1 Hz), 39.8. HRMS (ESI) m/z [M + Na + ] Calcd for C20H17D3N2O2Na 346.1611; Found 346.1608. REFERENCES
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